Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Jun 24, 2024

Experts: Guozhen Wang,Xiaoxin Ma,Weichang Huang,Shuanghu Wang,Anni Lou,Jun Wang,Yingfeng Tu,Wanfu Cui,Wangmei Zhou,Wenyong Zhang,Yue Li,Shiyu Geng,Ying Meng,Xu Li

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.
© 2024. The Author(s).

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ABOUT THE EXPERTS

Guozhen Wang,Xiaoxin Ma,Weichang Huang,Shuanghu Wang,Anni Lou,Jun Wang,Yingfeng Tu,Wanfu Cui,Wangmei Zhou,Wenyong Zhang,Yue Li,Shiyu Geng,Ying Meng,Xu Li

Guozhen Wang

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.

Xiaoxin Ma

Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, China.

Weichang Huang

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Shuanghu Wang

Central Laboratory, Wenzhou Medical University Lishui Hospital, Lishui People’s Hospital, Lishui, Zhejiang 323000, China.

Anni Lou

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Jun Wang

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Yingfeng Tu

School of Pharmaceutical Science, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.

Wanfu Cui

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Wangmei Zhou

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Wenyong Zhang

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Yue Li

Department of Intensive Care Unit, General Hospital of Southern Theatre Command, Southern Medical University, Guangzhou 510515, China.

Shiyu Geng

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Ying Meng

Department of Respiratory Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. nfyymengy@163.com.

Xu Li

Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. mylx99@smu.edu.cn.

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Southern Medical University, Guangzhou, 510515, Guangdong, China. mylx99@smu.edu.cn.